All Research Publications


 

Lectures (PDF Presentations) and Publications of any type

The intellectual property rights (including without limitation copyright and database rights) are owned by Dr Leonard Weinstock.

The content may be downloaded for personal, non-commercial use only. In all other cases, content originally published on the website may only be reproduced, stored, published or otherwise distributed in any form, with the written prior permission of Dr Leonard Weinstock.


Click the link below each title to see all of the articles

  • Decreasing recurrent bowel obstructions, improving quality of life with physiotherapy: a controlled study
    [Open Link to full article in New Page] (World Journal of Gastroenterology — 2018)
  • Small intestinal bacterial overgrowth (SIBO) and irritable bowel syndrome (IBS) in general
[Expand to Read More]

- Review of SIBO

- Review of IBS Treatment

- IBS Emergence of New Diagnostic and Treatment Options

- Long-Term Outcome of Rifaximin Therapy in Non-Constipation IBS

- Treatment of IBS SIBO

- Serum-Derived Bovine Immunoglobulin/Protein Isolate Therapy for Patients with Refractory Irritable Bowel Syndrome

- Podcast: LDN, Autoimmunity, and How SIBO Causes Symptoms Outside of the Gut with Dr. Leonard Weinstock

  • Integrative Gastroenterology Textbook - Chapter: Systemic manifestations of gastrointestinal diseases
    [Open Link in New Page]
  • Restless legs syndrome and SIBO
[Expand to Read More]

- Celiac Disease and RLS

- Celiac Disease is Associated with Restless Legs Syndrome

Crohn's Disease and RLS

- Crohn's Disease is Associated with Restless Legs Syndrome

- Restless Legs Syndrome: Theoretical Roles of Inflammatory and Immune Mechanisms

- Restless Legs Syndrome in Patients with Irritable Bowel Syndrome: Response to Small Intestinal Bacterial Overgrowth Therapy

- Rifaximin treatment of RLS – open label study

- RLS abstract Double-blind Brazil 

- RLS abstract Open Label Study Brazil

- RLS and SIBO Abstract APSS

- Treatment of Primary RLS with Rifaximin

- Treatment of RLS in IBS SIBO

- RLS: Sequential Treatment with Rifaximin and Low Dose Naltrexone

- RLS: Low Dose Naltrexone Treatment with/or without Rifaximin - 2017 report

A review of patient records who were treated in our office for RLS between 2015 and 2016 led to the following information. A total of 77 patients were seen for RLS (57 women and 20 men, average age of 56).

Questionnaires were mailed to all: 59 (77.6%) returned the questionnaire. The patients rated their response to each therapy as either marked improvement, moderate improvement, mild improvement, or no help.

Rifaximin was prescribed to 27 of the 59 patients. Low dose naltrexone was prescribed to 37 of the 59 patients.

Response to rifaximin was as follows: marked improvement in 8, moderate improvement in 2, mild improvement in 10, or no help in 6. The percentage of patients who were in a combination of the marked and moderate improvement was 57%.

Response to naltrexone was as follows: marked improvement in 15, moderate improvement in 6, mild improvement in 6, or no help in 10. The percentage of patients who were in a combination of the marked and moderate improvement was 63%.

6 of 37 (16%) patients who were prescribed naltrexone stopped the medication owing to side effects (insomnia, headache, shaky feeling).

Many of these patients had failed other medications for RLS and thus finding a nice response over 50% is a good finding.

- RLS and Gastrointestinal diseases – textbook chapter

« Return to RLS Clinic home page

  • Rosacea: links to SIBO and Crohn's disease
[Expand to Read More]

- Ocular Rosacea: Treatment with Rifaximin, a Non-Systemic Antibiotic

- Rosacea and Crohn's Disease

- Rosacea and small intestinal bacterial overgrowth: prevalence and response to rifaximin – Weinstock, MD & Steinhoff, MD

Parodi A, Paolino S, Greco A, Drago F, Mansi C, Rebora A, Parodi A, Savarino V. Small intestinal bacterial overgrowth in rosacea: clinical effectiveness of its eradication. Clin Gastroenterol Hepatol. 2008 Jul;6(7):759-64. doi: 10.1016/j.cgh.2008.02.054.

BACKGROUND & AIMS: To better understand the role of small intestinal bacterial overgrowth (SIBO) in rosacea, we aimed to assess the presence of SIBO in patients with rosacea and the clinical effectiveness of its eradication.

METHODS: We enrolled 113 consecutive rosacea ambulatory patients (31 M/82 F; mean age, 52 +/- 15 years) and 60 healthy controls who were sex- and age-matched. Patients and controls underwent lactulose and glucose breath tests (BTs) to assess the presence of SIBO. Patients positive for SIBO were randomized to receive rifaximin therapy (1200 mg/day for 10 days) or placebo. A group of patients with negative BTs were also treated with rifaximin. Eradication was assessed 1 month after the end of therapy. Two dermatologists, unblinded on therapy, evaluated rosacea patients before and after treatment on the basis of an objective scale.

RESULTS: The prevalence of SIBO was higher in patients than controls (52/113 vs 3/60, P < .001). After eradication, cutaneous lesions cleared in 20 of 28 and greatly improved in 6 of 28 patients, whereas patients treated with placebo remained unchanged (18/20) or worsened (2/20) (P < .001). Placebo patients were subsequently switched to rifaximin therapy, and SIBO was eradicated in 17 of 20 cases. Fifteen had a complete resolution of rosacea. After antibiotic therapy, 13 of 16 patients with negative BTs for SIBO remained unchanged, and this result differed from SIBO-positive cases (P < .001).

CONCLUSIONS: This study demonstrated that rosacea patients have a significantly higher SIBO prevalence than controls. Moreover, eradication of SIBO induced an almost complete regression of their cutaneous lesions and maintained this excellent result for at least 9 months.

  • Interstitial cystitis and SIBO
[Expand to Read More]

- Treatment of Interstitial Cystitis with Xifaxan

  • Inflammatory bowel disease, Crohn's disease and ulcerative colitis
[Expand to Read More]

- Hydroxychloroquine for Crohn’s Disease and Ulcerative Colitis

- Naltrexone Therapy for Crohn's Disease and Ulcerative Colitis

  • Low Dose Naltrexone (LDN) – articles and education
[Expand to Read More]

- Low-Dose Naltrexone for the Treatment of Sarcoidosis

- BMJ Treatment of POTS and MCAS with LDN IVIg and Antibiotics

- Small Intestinal Bacterial Overgrowth and Obstructive Sleep Apnea

- LDN Research Trust

- Low Dose Naltrexone Fact Sheet

- Consent for and Understanding Low Dose Naltrexone

- Naltrexone Side Effects and Efficacy in GI Disorders

- Naltrexone Therapy for Crohn's Disease and Ulcerative Colitis

- Naltrexone for Relief of Chronic Pain

- Dr. Weinstock Interview on LDN - Naltrexone - 2015

- Dr. Weinstock Interview on LDN - Naltrexone - 2017

- Low Dose Naltrexone and Cancer Therapy (PDF)

- LDN treatment for diet-refractory dermatitis herpetiformis in a patient with celiac disease and Ehlers-Danlos syndrome. (PDF)

Lectures (PDF Presentations) and Publications of any type

The intellectual property rights (including without limitation copyright and database rights) are owned by Dr Leonard Weinstock.

The content may be downloaded for personal, non-commercial use only. In all other cases, content originally published on the website may only be reproduced, stored, published or otherwise distributed in any form, with the written prior permission of Dr Leonard Weinstock.

- Low Dose Naltrexone and treatment of Psoriasis

- Low Dose Naltrexone and Autoimmune Disease Therapy

- Low Dose Naltrexone and Complex Regional Pain Syndrome

- LDN for Autoimmune and Inflammatory Diseases

- New Use for LDN: Sarcoidosis

- Low Dose Naltrexone: Motility Effects

- Low Dose Naltrexone Mechanisms of Action and Clinical Applications (Portland Lecture 2014)

- Low Dose Naltrexone Update 2016

- Is Restless Legs Syndrome an Inflammatory Disease?

- Ulcerative Colitis: LDN Rx

- Interview by Dr. Younger on LDN and neuroinflammation causing pain (Website link opens in new window)

  • Colonoscopy and Endoscopy - Techniques and Novel Findings
[Expand to Read More]

- Chicken Skin Mucosal in the Colon

- Trendelenberg Positioning for Colonoscopy

- Resect and discard approach to diminutive colonic polyps: Real world applicability amongst both academic and community gastroenterologists

- Duodenal Lipomatosis

- Pseudomelanosis of the duodenum

- Treatment of acute colonic pseuoobstruction with methylnaltrexone

  • Colonic Pseudo-Obstruction
[Expand to Read More]

Weinstock LB, Chang AC. Methylnaltrexone for treatment of acute colonic pseudo-obstruction. J Clin Gastroenterol. 2011;45:883-4.

Acute colonic pseudo-obstruction (ACPO) or Ogilvie syndrome is an idiopathic syndrome of dilation of the colon without mechanical obstruction that develops in hospitalized patients usually in the setting of significant medical and surgical conditions. Standard care therapy includes colonoscopic decompression or neostigmine. The latter is not Food and Drug Administration-approved for this indication but has been the recent intervention of choice. A patient with ACPO failed 2 injections of neostigmine. A clinical trial of subcutaneous methylnaltrexone was administered because she was on opioid therapy. There was a brisk response to methylnaltrexone, a μ-opioid-receptor antagonist which does not cross the blood-brain barrier. This is the first case report in the literature and in the pharmaceutical company's data bank that illustrates a potential role for methylnaltrexone in ACPO. Prospective, larger studies to determine the role of methylnaltrexone in ACPO are warranted..

  • Complex Regional Pain Syndrome and Ehlers-Danlos Syndrome
[Expand to Read More]

Identification and treatment of new inflammatory triggers for complex regional pain syndrome: small intestinal bacterial overgrowth and obstructive sleep apnea

Weinstock LB, Myers TL, Walters, AS, Schwartz, OA, Younger JW, Chopra PJ, Guarino AH.

ABSTRACT

Complex regional pain syndrome (CRPS) is evoked by conditions which may be associated with local and/or systemic inflammation. We present a case report of long-standing CRPS in an Ehlers-Danlos patient where prolonged remission was attained by directing therapy towards concomitant small intestinal bacterial overgrowth (SIBO), obstructive sleep apnea (OSA), and potential increased microglia activity. We theorize that cytokine production produced by SIBO and OSA may act as stimuli for ongoing CRPS symptoms. CRPS may also benefit from the properties of low dose naltrexone (LDN) which blocks microglia Toll-like receptors and induces production of endorphins which regulate and reduce inflammation.

INTRODUCTION

Complex regional pain syndrome (CRPS), formally known as reflex sympathetic dystrophy, is a neuropathic pain disorder that may fail to respond to current therapy including a variety of medications, nerve blocks, and ketamine infusions (1, 2). The incidence of CRPS is uncertain as there are few epidemiological studies. In the Mayo Clinic study, the rate was 5.46 per 100,000 person years in comparison to a 6-fold larger study in the Netherlands where the rate was 26.2 per 100,000 person years (3, 4). A marked female predominance was noted in each study. A familial occurrence of CRPS has been described (5). The natural history of CRPS varies widely. The Mayo Clinic reported that 56 of the 74 patients with CRPS for 1 month - 5 years had complete remission after various treatments. Spontaneous remission was observed when the initial symptoms were mild (3). By way of comparison, there were no remissions in 656 Drexel University patients who had CRPS for 1 - 46 years (6). Pain had only modest improvement with their treatments. No spontaneous remissions occurred in 102 Dutch database patients who had CRPS for 2.1 - 10.8 years (7). Progressive disease was reported in 16% and permanent disability was present in 31% of the Dutch patients.

Pathophysiological consequences of cytokine release, microglia activation, central sensitization, and autonomic nervous system dysfunction result in regional pain along with vasomotor, motor/trophic, and sudomotor/edema dysfunction (1, 2, 8, 9). Microglia cells are an integral part of the anatomic framework of the nervous system with attachments to astrocytes (10). They act as neuromodulators which alter central nervous cell and spinal sensory neuron excitability. Various syndromes marked by hyperalgesia including fibromyalgia and CRPS may be mediated by microglia cell activation as a consequence of pro-inflammatory cytokines (11, 12). Events known to evoke CRPS include bone fractures, sprains, trauma (injections, nerve injury, surgery, burns, and frostbite), nerve injury, infection, stroke, myocardial infarction, and pregnancy (1, 2). Many of these triggers may be associated with local and/or systemic inflammation (13 - 16). Therefore it is theoretically possible that cytokine release by these disorders could act as mediators for CRPS via activation of microglia. Parkitny et al performed a systematic and meta-analysis review of the role of inflammation in acute and chronic CRPS (17). In the former, serum interleukin-8 and tumor necrosis factors are increased. In the latter, there are many inflammatory markers in serum, blister fluid, and the cerebral spinal fluid. All of the Mayo Clinic patients reported an antecedent event, with bone fracture being the most common trigger (46%) (3). Fractures are associated with elevated cytokines and C-reactive protein in animal models (13). Chronic systemic inflammation has been shown to be an independent risk factor for bone fractures in humans (14), thus a fracture that precipitates CRPS may stem from a pre-existing chronic inflammatory state.

Since the pathophysiology of CRPS is not clear and no single therapy is effective, it is desirable to consider all theories. We present a case report of long-standing CRPS in a patient with Ehlers-Danlos where prolonged remission was attained by directing therapy towards concomitant small intestinal bacterial overgrowth (SIBO), obstructive sleep apnea (OSA), and potential increased microglia activity. We theorize that cytokine production produced by SIBO and OSA act as stimuli for ongoing CRPS symptoms. Written consent was obtained from the patient to publish this article.

Case Report

A 56 year-old Caucasian woman had continuous severe leg pain with episodic pain in the arms and nose since May 2005. Pain first started in the right groin after a cardiac catheterization for evaluation of atypical chest pain. After 5 months, the pain had spread down her leg. Asymmetric, shiny skin with fluctuating temperature changes (up to 10o Fahrenheit), color change, and edema developed. The continuous leg pain worsened 2 years later when she had a spontaneous right ankle fracture. Severe skin blistering occurred beneath the cast. Mild to moderate arm and nose pain subsequently occurred mainly in cold weather. Diagnosis of CRPS was confirmed by four pain management centers. The patient failed sympathetic ganglion blocks and gabapentin. Prolonged use of opioids worsened the pain.

A 45-year history of irritable bowel syndrome was characterized by post-prandial bloating, excessive and foul flatus, and diarrhea. Fatigue, anxiety, and a sleep disorder were present for several years prior to the onset of CRPS. A 2010 sleep laboratory polysomnography evaluation was reviewed. This had been performed to evaluate snoring, daytime hypersomnolence, morning headaches, and awakening with gasping for breath. The Apnea-Hypopnea Index was 15 with a Respiratory Disturbance Index of 58 (documentation of desaturation was not available). In 2010 implementation of nasal mask CPAP at 12 cm H2O was performed. Despite CPAP use, symptoms of sleep apnea continued and intolerance of the device resulted in reduction of CPAP use. Periodic use of alprazolam, bupropion, and nortriptyline increased the depth of sleep and reduced anxiety, but did not improve fatigue and sleep apnea symptoms.

In October 2013 the patient returned for a second evaluation for atypical chest pain and fatigue. Sleep Medicine was asked to consult again. Gastroenterology was consulted for the first time. The blood pressure was 130/80 mm Hg and pulse 80 beats per minute. Body mass index was 29.3 kg/m2. There was diffuse mild abdominal tenderness. Edema, blue discoloration, and tenderness were present in the right leg (Fig. 1). She exhibited joint hypermobility with the Ehlers-Danlos syndrome Beighton joint flexibility score of 8/9. The patient met 3 major criteria and 5 minor Villefranche criteria diagnostic for the hypermobility type of Ehlers-Danlos syndrome (18). This diagnosis was supported by her family history where 3 generations had many features of Ehlers-Danlos syndrome. The C-reactive protein was elevated at 3.9 mg/L (normal range: 1.0-3.0). A hiatus hernia was diagnosed by endoscopy. Small intestinal bacterial overgrowth was diagnosed by a lactulose breath test. A repeat sleep laboratory evaluation was performed and BiPAP titration was completed with optimal settings of 15/11 with nasal mask. Rifaximin was given for SIBO (1650 mg/day/2-weeks) and long-term low dose naltrexone (LDN) (4.5 mg/daily) was prescribed based on success in a prior publication (19).

At the 1-month gastroenterology clinic visit, she reported a marked improvement in her leg and bowel symptoms. LDN was continued long-term. At the 3-month Sleep Medicine clinic visit, interrogation of the sleep apnea device over 90 days revealed 82% use >4 hours with 6 hours average use per night. At a 16-month gastroenterology clinic visit she returned with complaints of 1 month of bloating, fatigue, and episodic minor attacks of pain in the arms and nose in cold weather. Inadequate treatment of sleep apnea was suspected as the patient revealed she would often have nightmares and in the morning she would find her BiPAP device on the floor. There was mild diffuse abdominal tenderness. Complete remission of CRPS was noted in the right leg (Fig. 2). Naltrexone was continued at 4.5 mg/day to maintain CRPS therapy and three therapies were added: 1) rifaximin (1650 mg/day for one month) to retreat SIBO; 2) erythromycin (50 mg/nightly long-term which acts as motilin-like hormone to stimulate the small intestinal migrating motor complex which reduces SIBO relapse) (20); and 3) Clonazepam (1 mg/nightly) to reduce nightmares to reduce the urge to remove the BiPAP device. Multiple communications over the following eight months revealed that there had been rapid and sustained remission of all CRPS pain, bowel symptoms, and fatigue. At the 6-month Sleep Medicine clinic visit,, interrogation of the BiPap device over 30 days documented improved to 100% use >4 hours with >7 hours average use per night.

Figure 1. October 2013: Asymmetric edema and discoloration in the right leg.

Figure 2. December 2014: Signs of CRSP have resolved. The scar from ankle surgery better visualized.

Discussion

In this case report, remission of CRPS was attained by directing therapy towards SIBO, OSA, and potential increased microglia activity. We theorize that cytokine production including tumor necrosis factor produced by SIBO (20) and OSA (21) may act as stimuli for ongoing CRPS symptoms.

There is a known relationship of CRPS and the gastrointestinal tract. Dysbiosis (alterations of the microbiome) and increased intestinal permeability have been reported in CRPS and these conditions also cause chronic systemic inflammation (22 – 24). Irritable bowel syndrome is common in CRPS although the relationship has hitherto not been elucidated (25). SIBO may be a pathological factor in up to 50% of irritable bowel syndrome patients and it can cause systemic inflammation and extra-intestinal disorders including fibromyalgia, restless legs syndrome, rosacea, and chronic pelvic pain syndromes (20). Treatment of both SIBO and irritable bowel syndrome with rifaximin, a non-absorbed, gut-directed antibiotic has been extensively studied (26). Experimental therapy of unregulated inflammation and microglia activation using low dose naltrexone (LDN) has been reported in pain disorders including two cases of CRPS (11, 19).

Ehlers-Danlos syndrome is a dominant inherited systemic disorder and the incidence may be as high as 2% of the population (18). This syndrome is commonly missed in childhood and adults may present with a unique set of problems that may leave physicians confounded as seen in our patient and her kindred. Published reports of concomitant CRPS and Ehlers-Danlos are rare (18, 27). The authors of the case series with four patients proposed that Ehlers-Danlos contributed to CRPS via stretch injury to nerves traversing hypermobile joints, increased fragility of nerve connective tissue, and/or nerve trauma from more frequent surgery (27). Subsequently, both syndromes have subsequently have been concurrently diagnosed in approximately 25% of one of the author's pain management practice (PJC).

Alternative mechanisms whereby Ehlers-Danlos syndrome contributes to CRPS are proposed. Ehlers-Danlos syndrome causes OSA owing to connective tissue laxity (28) and thus subsequent chronic hypoxia-induced inflammation (21) may contribute to CRPS activation. This mechanism appeared to play a role in our patient since complete remission of all CRPS symptoms was not attained until sleep apnea therapy was optimized. In addition, inflammation from SIBO (20) may contribute to CPRS activation. Gastrointestinal symptoms are common in both Ehlers-Danlos syndrome and in CRPS (29, 25). In Ehlers-Danlos syndrome, SIBO and small intestinal motility changes have been reported: dilated small intestinal diameter, small bowel diverticulosis, small intestinal motility disorders, and loose connective tissue in the mesentery that allows for drooping of the small intestine to create a relative blind loop (30 - 33). Defective collagen synthesis, ÃŽ±-actin deficiency, and autonomic dysfunction are potential explanations for abnormal motility (34, 35). SIBO may be common in CRPS since Goebel et al demonstrated that increased intestinal permeability was common in CRPS (23). A recent case report using long-term cephalosporin to keep CRPS in remission supports the idea that manipulation of the microbiome may play a role in CRPS therapy (36). Finally, the severity of CRPS may be enhanced in Ehlers-Danlos syndrome patients owing to central hypersensitivity (37).

In the case study herein, low dose naltrexone (LDN) was administered to attenuate microglia activation via blocking Toll-like receptors 2 and 4 (11, 19). In addition, LDN causes rebound met-enkephelin production which then regulates systemic inflammation by regulating T- and B-cell lymphocyte response and cytokine production which is important in CRPS (11, 17). This is now the third reported case where LDN has demonstrated improvement in CRPS symptoms (19). Subsequently, one of the authors (PJC) has employed this therapy frequently in his practice and has observed therapeutic benefit in CRPS patients. Administration of LDN as off-label use for pain control is experimental.

Limitations of this study include that CRPS symptoms might have gone into spontaneous remission although most patients suffer for many years (6, 7). The unremitting nature of this patient's symptoms and the rapid response to each course of therapy argue against this concern. Multimodality therapy was administered so it is unknown how much each contributed to remission of CRPS symptoms. Nonetheless, a multimodality approach by pain management physicians is commonplace (1).

Physicians may not be familiar with the SIBO link to irritable bowel syndrome and may be dismissed as an unrelated syndrome. OSA may go unrecognized since sleep disturbance is common in CRPS and is often blamed on pain. An epidemiological study of the prevalence of Ehlers-Danlos, SIBO, and OSA is required to further understand the roles that these conditions may play in CRPS. It is possible that undiagnosed Ehlers-Danlos syndrome in CRPS patients could also explain some cases of familial CRPS. We theorize that recognition and treatment of underlying causes of inflammation is likely to be an important future modality in CRPS.

REFERENCES

  1. Harden RN, Oaklander AL, Burton AW, Perez RS, Richardson K, Swan M, Barthel J, Costa B, Graciosa JR, Bruehl S. Complex regional pain syndrome: practical diagnostic and treatment guidelines, 4th edition. Pain Med 2013;14:180-229.
  2. Borchers AT, Gershwin ME. Complex regional pain syndrome: A comprehensive and critical review. Autoimmunity Reviews 2014;13:242-5.
  3. Sandroni P, Benrud-Larson LM, McClelland RL, Low PA. Complex regional pain syndrome type I: incidence and prevalence in Olmsted County, a population-based study. Pain 2003;103:199-207.
  4. de Mos M, de Bruijn AG, Huygen FJ, Dieleman JP, Ch. Stricker BH, Sturkenboom MC. The incidence of complex regional pain syndrome: a population-based study. Pain 2007;129:12-20.
  5. de Rooij AM, de Mos M, Sturkenboom MC, Marinus J, van den Maagdenberg AM, van Hilten JJ. Familial occurrence of complex regional pain syndrome. Eur J Pain 2009;13:171-7.
  6. Schwartzman RJ, Erwin KL, Alexander GM. The natural history of complex regional pain syndrome. Clin J Pain 2009;25:273-280.
  7. de Mos M, Huygen FJ, van der Hoeven-Borgman M, Dieleman JP, Ch. Stricker BH, Sturkenboom MC. Outcome of the complex regional pain syndrome. Clin J Pain 2009;25:590-7.
  8. Wieseler-Frank J, Maier SF, Watkins LR. Immune-to-brain communication dynamically modulates pain: physiological and pathological consequences. Brain Behav Immun 2005;19:104-11.
  9. Schlereth T, Drummond PD, Birklein F. Inflammation in CRPS: role of the sympathetic supply. Auton Neurosci 2014;182:102-7.
  10. Lourbopoulos A, Ertürk A, Hellal F. Microglia in action: how aging and injury can change the brain's guardians. Front Cell Neurosci 2015;9:54.
  11. Younger J, Parkitny L, McLain D. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clin Rheumatol 2014;33:451-9.
  12. Del Valle L, Schwartzman RJ, Alexander G. Spinal cord histopathological alterations in a patient with longstanding complex regional pain syndrome. Brain Behav Immun 2009:23:85-91.
  13. Hadjiargyrou M, O’Keefe RJ. The convergence of fracture repair and stem cells: interplay of genes, aging, environmental factors and disease. J Bone Miner Res 2014;29:2307-22.
  14. Dahl K, Ahmed LA, Joakimsen RM, Jørgensen L, Eggen AE, Eriksen EF, Bjørnerem Å. High-sensitivity C-reactive protein is an independent risk factor for non-vertebral fractures in women and men: The Tromsø Study. Bone 2015;72:65-70.
  15. Hristov M, Weber C. Myocardial infarction and inflammation: lost in the biomarker labyrinth. Circ Res 2015;116:781-3.
  16. Szarka A, Rigó J Jr, Lázár L, Beko G, Molvarec A. Circulating cytokines, chemokines and adhesion molecules in normal pregnancy and preeclampsia determined by multiplex suspension array. BMC Immunol 2010;11:59.
  17. Parkitny L, McAuley JH, Di Pietro F, Stanton TR, O'Connell NE, Marinus J, van Hilten JJ, Moseley GL. Neurology 2013;80:106-17.
  18. Castori, M. Ehlers-Danlos syndrome, hypermobility type: an underdiagnosed hereditary connective tissue disorder with mucocutaneous, articular, and systemic manifestations. Review article. ISRN Dermatol 2012:1768-90..
  19. Chopra P, Cooper MS. Treatment of complex regional pain syndrome (CRPS) using low dose naltrexone (LDN). J Neuroimmune Pharmacol 2013;8:470-6.
  20. Turnbull LK, Mullin GE, Weinstock LB. Principles of Integrative astroenterology: Systemic Signs of Underlying Digestive Dysfunction and Disease. In: Mullen G (ed.), Integrative Gastroenterology. Weil Integrative Medical Library, Oxford University Press, 2011; pp 84-98.
  21. Arnaud C, Dematteis M, Pepin JL, Baguet JP, Lévy P. Obstructive sleep apnea, immuno-inflammation, and atherosclerosis. Semin Immunopathol 2009;31:113-25.
  22. Reichenberger ER, Alexander GM, Perreault MJ, Russell JA, Schwartzman RJ, Hirschberg U, Rosen G. Establishing a relationship between bacteria in the human gut and complex regional pain syndrome. Brain Behav Immunol 2013;29:62-9.
  23. Goebel A, Buhner S, Schedel R, Lochs H, Sprotte G. Altered intestinal permeability in patients with primary fibromyalgia and in patients with complex regional pain syndrome. Rheumatol 2008;47:1223-7.
  24. Tojo R, Suárez A, Clemente MG, de los Reyes-Gavilán CG, Margolles A, Gueimonde M, Ruas-Madiedo P. Intestinal microbiota in health and disease: role of bifidobacteria in gut homeostasis. World J Gastroenterol 2014;20:15163–76.
  25. Birley T, Goebel A. Widespread pain in patients with complex regional pain syndrome. PainPract 2014;14:526-31.
  26. Schoenfeld P, Pimentel M, Chang L, Lembo A, Chey WD, Yu J, Paterson C, Bortey E, Forbes WP. Safety and tolerability of rifaximin for the treatment of irritable bowel syndrome without constipation: a pooled analysis of randomised, double-blind, placebo-controlled trials. Aliment Pharmacol Ther 2014;39:1161-8.
  27. Stoler JM, Oaklander AL. Patients with Ehlers Danlos syndrome and CRPS: a possible association? Pain 2006;123:204-9.
  28. Guilleminault C, Primeau M, Chiu HY, Yuen KM, Leger D, Metlaine A. Sleep-disordered breathing in Ehlers-Danlos syndrome: a genetic model of OSA. Chest 2013;144:1503-11.
  29. Fikree A, Grahame R, Aktar R, Farmer AD, Hakim AJ, Morris JK, Knowles CH, Aziz Q. A prospective evaluation of undiagnosed joint hypermobility syndrome in patients with gastrointestinal symptoms. Clin Gastroenterol Hepatol 2014;12:1680-7.
  30. Hines C Jr, Davis WD Jr. Ehlers-Danlos syndrome with megaduodenum and malabsorption syndrome secondary to bacterial overgrowth. A report of the first case. Am J Med 1973; 54:539-43.
  31. Harris RD. Small bowel dilatation in Ehlers-Danlos syndrome--an unreported gastrointestinal manifestation.Br J Radiol 1974;47:623-7.
  32. McLean AM, Paul RE Jr, Kritzman J, Farthing MJ. Malabsorption in Marfan (Ehlers-Danlos) syndrome. J Clin Gastroenterol 1985;7:304-8.
  33. Reinstein E, Pimentel M, Pariani M, Nemec S, Sokol T, Rimoin DL. Visceroptosis of the bowel in the hypermobility type of Ehlers-Danlos syndrome: presentation of a rare manifestation and review of the literature. Eur J Med Genet 2012;55:548-51.
  34. Pelizzo G, Villanacci V, Salemme M, Nakib G, Calcaterra V, Bassotti G. Intestinal pseudo-obstruction due to small bowel ÃŽ±-actin deficiency in a child with Ehlers-Danlos syndrome. Tech Coloproctol 2013;17:673-4.
  35. Benarroch E. Postural tachycardia syndrome: a heterogeneous and multifactorial disorder. Mayo Clin Proc 2012;87:1214-25.
  36. Ware MA, Bennett GJ. Case report: Long-standing complex regional pain syndrome relieved by a cephalosporin antibiotic. Pain 2014;155:1412-5.
  37. Rombaut L, Scheper M, De Wandele I, De Vries J, Meeus M, Malfait F, Engelbert R, Calders P. Chronic pain in patients with the hypermobility type of Ehlers-Danlos syndrome: evidence for generalized hyperalgesia. Clin Rheumatol 2015;34:1121-9.

Keywords: LDN